Polyunsaturated fatty acid monoglycerides, derivatives, and uses thereof

ABSTRACT

There are provided various polyunsaturated fatty acid monoglycerides and derivatives thereof. These compounds can be useful as cancer chemopreventive agents, cancer treating agent, inhibiting tumor growth or cell proliferation, reducing tumor growth or as radioenhencers for radiotherapy of cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of PCT internationalpatent application No. PCT/CA2008/000301 filed on Feb. 14, 2008, whichclaims priority on U.S. provisional application No. 60/889,984 filed onFeb. 15, 2007. These applications are incorporated herein by referencein their entirety.

FIELD OF THE DISCLOSURE

The present document relates to the field of medicinal chemistry. Moreparticularly it relates to the field of active agents used as cancerchemopreventive agent and radioenhencer for radiotherapy of cancer.

BACKGROUND OF THE DISCLOSURE

An estimated 153,100 new cases of cancer and 70,400 deaths from cancerwill occur in Canada in 2006. Men outnumber women for both new cases anddeaths, by 5% for incidence and 11% for mortality. Three types of canceraccount for at least 55% of new cases in each sex: prostate, lung, andcolorectal cancers in males, and breast, lung, and colorectal cancers infemales. Twenty nine percent of cancer deaths in men and 26% in womenare due to lung cancer alone. On the basis of current incidence rates,38% of Canadian women and 44% of men will develop cancer during theirlifetimes. On the basis of current mortality rates, 24% of women and 29%of men, or approximately 1 out of every 4 Canadians, will die fromcancer (Canadian cancer society, 2006).

Over the past two decades the Division of Cancer Prevention of the USNational Cancer Institute has organized a research and developmentprogram for the clinical evaluation of potential cancer preventiveagents. The NCI define chemoprevention as an innovative area of cancerresearch that focuses on the prevention of cancer through pharmacologic,biologic, and nutritional interventions. As originally described, thisinvolves the primary prevention of initiation and the secondaryprevention, delay, or reversal of promotion and progression (Crowell J.A., and al., European Journal of Cancer 41, 2005).

Epidemiological studies have shown a correlation between high fatconsumption and an increased risk of breast cancer (Wynder E L, Cancer,58, 1986). In addition, both the type and amount of dietary fat appearto affect development of breast cancer (Bartsch H, and al.Carcinogenesis 20, 1999). A relatively high intake of n-6polyunsaturated fatty acids (PUFAs) is considered to be a risk factorand is associated with a more advanced stage of the disease at the timeof diagnosis (Nomura A M, and al., Breast Cancer Res Treat 18, 1991) andreduced survival (Rohan T E, and al., Nutr Cancer, 20, 1993). Incontrast, an inverse relationship exists between the incidence of breastcancer and the level of fish consumption, suggesting a protective rolefor n-3 PUFAs in human breast cancer.

A diet containing LA (n-6 PUFA) stimulated the growth and metastasis ofhuman breast cancer cells transplanted into athymic nude mice, whereasEPA or DHA exerted suppressive effects compared with palmitic acid (PA).Thus, in agreement with the epidemiological observations, LA (n-6 PUFA)accelerates, whereas EPA and DHA (n-3 PUFA) suppress mammary cancercompared with PA diet in experimental systems (Rose D P, and al., JNCI87, 1995) (Senzaki H, and al., Anticancer Res 18, 1998).

SUMMARY OF THE DISCLOSURE

According to one aspect there are provided compounds of formulas (I),(II), (III), and (IV):

wherein

-   -   X₁ is O, NH, or S;    -   X₂ is O, NH, or S;    -   X₃ is O, NH, or S;    -   R₁ and R₂ each independently represents —H, —C(O)NH₂, —S(O)NH₂,        —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22        (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl,        —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl        unsubstituted or substituted with at least one substituent        chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,        —C6-C12 aryl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl,        —C8-C22 (aryl)alkynyl, three- to seven-membered non-aromatic        heterocycle unsubstituted or substituted with at least one        substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and        —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle        unsubstituted or substituted with at least one substituent        chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,        —(CH₂)_(n) amino acid wherein the amino acid is connected        through its alpha carbon atom, —(CH₂)_(n) peptide wherein the        peptide is connected through the alpha carbon atom of one of its        amino acids, —CH₂OR₅, —C(O)R₅, —C(O)OR₅, —C(O)NR₅, —P(O)(OR₅)₂,        —S(O)₂NHR₅, —SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a        sugar phosphate    -   or R₁ and R₂ are joined together so as to form a five- to        seven-membered non-aromatic heterocycle unsubstituted or        substituted with at least one substituent chosen from —C1-C22        alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate,        sulfate carbonyl group, or a thiocarbonyl imine;    -   R₅ is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22        (halo)alkyl, —C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl,        —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22        (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, —C1-C22 alkoxy, —C1-C22        (amino)alkyl, a —(C3-C7) cycloalkyl unsubstituted or substituted        with at least one substituent chosen from —C1-C22 alkyl, —C2-C22        alkenyl, and —C2-C22 alkynyl, a three- to seven-membered        non-aromatic heterocycle unsubstituted or substituted at least        one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and        —C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle        unsubstituted or substituted with at least one substituent        chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,        a —(CH₂)_(n) amino acid wherein the amino acid is connected to        the compound through its alpha carbon atom, a —(CH₂)_(n) peptide        wherein the peptide is connected to the compound through the        alpha carbon atom of one of its amino acids, a sugar or a sugar        phosphate; and    -   n is an integer having a value of 0, 1, 2, 3, or 4,        and pharmaceutically acceptable salts thereof.

According to another aspect there are provided compounds of formulas(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) or (XV):

-   -   X₁ is O, NH, or S;    -   X₂ is O, NH, or S;    -   X₃ is O, NH, or S;    -   R₃ and R₄ each independently represents —H, —C(O)NH₂, —S(O)NH₂,        —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22        (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl,        —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl        unsubstituted or substituted with at least one substituent        chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,        —C6-C12 aryl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl,        —C8-C22 (aryl)alkynyl, three- to seven-membered non-aromatic        heterocycle unsubstituted or substituted with at least one        substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and        —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle        unsubstituted or substituted with at least one substituent        chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,        —(CH₂)_(n) amino acid wherein the amino acid is connected        through its alpha carbon atom, —(CH₂)_(n) peptide wherein the        peptide is connected through the alpha carbon atom of one of its        amino acids, —CH₂OR₅, —C(O)R₄, —C(O)OR₄, —C(O)NR₄, —P(O)(OR₅)₂,        —S(O)₂NHR₅, —SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a        sugar phosphate,    -   or R₃ and R₄ are joined together so as to form a five- to        seven-membered non-aromatic heterocycle unsubstituted or        substituted with at least one substituent chosen from —C1-C22        alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate,        sulfate carbonyl group, or a thiocarbonyl imine;    -   R₅ is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22        (halo)alkyl, —C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl,        —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22        (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, —C1-C22 alkoxy, —C1-C22        (amino)alkyl, a —(C3-C7) cycloalkyl unsubstituted or substituted        with at least one substituent chosen from —C1-C22 alkyl, —C2-C22        alkenyl, and —C2-C22 alkynyl, a three- to seven-membered        non-aromatic heterocycle unsubstituted or substituted at least        one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and        —C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle        unsubstituted or substituted with at least one substituent        chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,        a —(CH₂)_(n) amino acid wherein the amino acid is connected to        the compound through its alpha carbon atom, a —(CH₂)_(n) peptide        wherein the peptide is connected to the compound through the        alpha carbon atom of one of its amino acids, a sugar or a sugar        phosphate; and    -   n is an integer having a value of 0, 1, 2, 3, or 4;        and pharmaceutically acceptable salts thereof.

It was found that such compounds can be used so as to reduce or inhibittumor growth, or inhibit tumor cell proliferation in vitro as well as invivo. It was also found that the compounds previously mentioned can beuseful as cancer chemopreventive agents (for example breast cancer,prostate cancer, colon cancer and lung cancer). The compounds of thepresent disclosure can be used separately or in a mixture of at leasttwo of them (for example 2, 3 or 4 of them). The compounds of thepresent disclosure can also be in isolated form. The compounds of thepresent disclosure can be used as a composition which also includes apharmaceutically acceptable carrier.

It was also found that the compounds previously mentioned can provideeffective pharmaceutical compositions for chemoprevention of cancer.Such compositions can comprise at least two compounds chosen fromcompounds of formulas (I), (II), (III), and (IV).

The compounds and compositions of the present disclosure can also beeffective as radioenhencers for radiotherapy of cancer, or incombination with a pharmaceutically active ingredient in chemotherapy ofcancer.

The compounds and compositions of the present disclosure can beeffective for chemoprevention of various types of cancers (such asbreast cancer, lung cancer, prostate cancer, colon cancer). Tumorsgrowth of such types of cancer can be inhibited or reduced with thesecompounds.

The compounds and compositions of the present disclosure can be used fortreating cancer (for example breast cancer, lung cancer, prostatecancer, colon cancer).

According to another aspect there is provided a method forchemopreventing cancer comprising the step of administering to a subjectan effective amount of at least one compound chosen from compounds offormulas (I), (II), (III), (IV), (V), (VI), (VII), (VII), (IX), (X),(XI), (XII), (XIII), (XIV) and (XV).

According to another aspect there is provided a method for inhibitingtumor growth, inhibiting tumor cell proliferation, or reducing tumorgrowth, in vitro or in vivo, comprising contacting the tumor with aneffective amount of a at least one compound chosen from compounds offormulas (I), (II), (III), (IV), (V), (VI), (VII), (VII), (IX), (X),(XI), (XII), (XIII), (XIV) and (XV).

According to another aspect there is provided a method of reducing tumorgrowth in a subject comprising administering to the subject an effectiveamount of at least one compound chosen from compounds of formulas (I),(II), (III), (IV), (V), (VI), (VII), (VII), (IX), (X), (XI), (XII),(XIII), (XIV) and (XV).

According to another aspect there is provided a method for treatingcancer (for example breast cancer, lung cancer, prostate cancer, coloncancer) comprising administering to the subject in need thereof aneffective amount of at least one compound chosen from compounds offormulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV) and (XV).

BRIEF DESCRIPTION OF THE FIGURES

Further features and advantages of the disclosure will become morereadily apparent from the following description of specific embodimentsas illustrated by way of examples in the appended figures wherein:

FIG. 1 is a diagram showing the results of an in vitro assay of acomposition according to an embodiment of the present disclosure,wherein the assay was carried out on A549 human cancer cell line;

FIG. 2 is a diagram showing the results of an in vitro assay of acomposition according to an embodiment of the present disclosure,wherein the assay was carried out on PC3 human cancer cell line;

FIG. 3 is a diagram showing the results of an in vitro assay of acomposition according to an embodiment of the present disclosure,wherein the assay was carried out on HCT-15 human cancer cell line;

FIG. 4 is a diagram showing the results of an in vitro assay of acomposition according to an embodiment of the present disclosure,wherein the assay was carried out on BT-549 human cancer cell line;

FIG. 5 is a curve representing the results of a comparative in vivoefficacy study of a composition according to an embodiment of thepresent disclosure, wherein the study was carried out on (NU/NU-Fox1nu)mice xenograft model;

FIG. 6 is a curve representing the body weight of (NU/NU-Fox1nu) micemodel as a function of days of post inoculation in the in vivo efficacystudy of FIG. 5;

FIG. 7 represents a comparative human absorption cross-over study of twodifferent compositions containing docosahexaenoic acid (DHA) which are afish oil and a composition according to another example;

FIG. 8 represents a comparative human absorption cross-over study of twodifferent compositions containing omega-3 docosapentaenoic acid (DPAω3)which are a fish oil and a composition according to another example; and

FIG. 9 represents an in vitro assay of a composition according to anexample, wherein the assay was carried out on human THP-1 monocyte cell.

DETAILED DESCRIPTION OF THE DISCLOSURE

Further features and advantages of the previously-mentioned compoundswill become more readily apparent from the following description ofnon-limiting examples.

According to another aspect there is provided a method for preparing acompound of formula (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII),(XIII), (XIV) or (XV), the method comprising reacting a compound offormula (XVI), (XVII), or (XVIII)

in which X₁, X₂, X₃, R₃ and R₄ are as previously defined,with at least one ester of at least one fatty acid chosen from

being understood that when a compound of formula (XVI) is used, acompound of formula (V), (VI), (VII), or (VIII) is obtained, when acompound of formula (XVII) is used, a compound of formula (IX), (X), or(XI) is obtained, and when a compound of formula (XVIII) is used, acompound of formula (XII), (XIII), (XIV) or (XV) is obtained.

For example, a compound of formula (XVI) and the fatty acid ester can bereacted together in the presence of a base (such as KOH or NaOH).Alternatively, they can be reacted together in the presence of an enzymefor example a lipase such as Candida antartica.

The method can further comprises treating the obtained compound offormula (V), (VI), (VII), or (VII) under acidic conditions so as to openits heterocycle ring and protonate X₂ and X₃.

For example, the compound of formula (XVI) can be

The method can further comprise treating the obtained compound offormula (V), (VI), (VII), or (VIII) under acidic conditions so as toobtain

The acidic conditions can be brought by an acid chosen from acetic acid,formic acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroaceticacid, perchloric acid and pyridinium tosylate or by an acidic resin.

The ester can be C1-C6 alkyl ester of the fatty acid. Alternatively theester can be a monoglyceride or a diglyceride in which at least one ofthe oxygen atom of the glycerol backbone forms an ester with the fattyacid. The ester can also be a triglyceride in which the three oxygenatoms of the glycerol backbone form an ester with one molecule of thefatty acid.

The ester can also be a diglyceride or triglyceride in which at leastone oxygen atoms of the glycerol backbone forms an ester with anotheromega-3 fatty acid or another omega-6 fatty acid.

For example, preparation of compounds of formulas (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV) can be carriedout by reacting together a fish oil which contains the triglyceride withthe compound of formula (V), (VI), (VII), (VIII), (IX), (X), (XI),(XII), (XIII), (XIV) or (XV).

In fact, various oils rich in omega-3 and/or omega-6 fatty acids can beused. For example, vegetal oils (such as flaxseed oil, pumpkinseed oil,canola oil, soybean oil, walnut oil, etc.) and marine oils (such asalgae oil, seal oil, krill oil, fish oil (for example cod liver oil,salmon oil, tuna oil, shark oil, pelagic fishes oil, sardine oil, etc))can be used.

The method can comprise reacting the compound of formula (XVI), (XVII),or (XVIII) with at least two different fatty acids chosen from the fattyacids previously defined. The method can also comprise reacting morethan one compound chosen from the compounds of formulas (XVI), (XVII),and (XVIII).

The term “aryl” as used herein refers to a cyclic or polycyclic aromaticring. For example, the aryl group can be phenyl or napthyl.

The expression “aromatic heterocycle” as used herein refers to anaromatic cyclic or fused polycyclic ring system having at least oneheteroatom selected from the group consisting of N, O, S and P.Non-limitative examples include heteroaryl groups are furyl, thienyl,pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl,pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl,benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl,isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.

The expression “non-aromatic heterocycle” includes non-aromatic rings orring systems that contain at least one ring having at least one heteroatom (such as nitrogen, oxygen, sulfur or phosphorus). This termincludes, in a non-limitative manner all of the fully saturated andpartially unsaturated derivatives of the above mentioned aromaticheterocycles groups. Examples of non-aromatic heterocycle groupsinclude, in a non-limitative manner, pyrrolidinyl, tetrahydrofuranyl,morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl,isothiazolidinyl, and imidazolidinyl.

The expression “inflammatory disease(s)” as used herein refers to all ofthe acute or chronic inflammatory diseases associated with the excessiverelease of cytokines, and complication thereof. The expression “chronicinflammatory disease(s)” refers to all diseases that induce tissueinjury or induce continuous inflammation due to hyperactivity and theexcessive release of cytokines, and complication thereof. In particular,the inflammatory diseases to which the compounds and compositions of thepresent disclosure can be applied are not limited to, but includeinflammatory bowel disease such as Crohn's disease and ulcerativecolitis, peritonitis, osteomyelitis, cellulitis, meningitis, cerebritis,pancreatitis, trauma-inducing shock, bronchial asthma, allergicrhinitis, cystic fibrosis, cerebral apoplexy, acute bronchitis, chronicbronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis,gout, spinal arthropathy, ankylosing spondylitis, Reiter's syndrome,psoriatic arthropathy, enteropathic spondylitis, juvenile arthropathy,juvenile ankylosing spondylitis, reactive arthropathy, infectiousarthritis, post-infectious arthritis, gonococcal arthritis, tuberculousarthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lymedisease, arthritis associated with ‘vasculitis syndrome’, polyarteritisnodosa, hypersensitivity vasculitis, Wegener's granulomatosis,polymyalgia rheumatica, giant cell arteritis, calcium crystal depositionarthropathy, pseudogout, non-joint rheumatism, bursitis, tenosynovitis,epicondylitis (tennis elbow), neuropathic joint disease (charcot joint),hemarthrosic, Henoch-Schonlein purpura, hypertrophic osteoarthropathy,multicentric reticulohistiocytoma, scoliosis, hemochromoatosis,meniscocytosis, other hemoglobinopathy, hyperlipoproteinemia,hypogammaglobulinaemia, familial Mediterranean fever, Gerhardt Disease,systemic lupus erythematosus, relapsing fever, psoriasis, multiplesclerosis, sepsis (septicemia), septic shock, acute respiratory distresssyndrome, multiple organ dysfunction syndrome, chronic obstructivepulmonary disease, rheumatic arthritis, acute lung injury,bronchopulmonary dysplasia and so on.

The expression “effective amount” of a compound of the presentdisclosure or of a composition of the present disclosure is a quantitysufficient to, when administered to the subject, including a mammal, forexample a human, effect beneficial or desired results, includingclinical results, and, as such, an “effective amount” or synonym theretodepends upon the context in which it is being applied. For example, inthe context of treating cancer, for example, it is an amount of thecompound sufficient to achieve such treatment of the cancer as comparedto the response obtained without administration of the compound. Theamount of a given compound of the present disclosure that willcorrespond to an effective amount will vary depending upon variousfactors, such as the given drug or compound, the pharmaceuticalformulation, the route of administration, the type of disease ordisorder, the identity of the subject or host being treated, and thelike, but can nevertheless be routinely determined by one skilled in theart. Also, as used herein, an “effective amount” of a compound of thepresent disclosure is an amount which inhibits, suppresses or reduces acancer (e.g., as determined by clinical symptoms or the amount ofcancerous cells) in a subject as compared to a control. The samedefinition of “effective amount” also applies when the compounds of thepresent disclosure are used for inhibiting tumor growth, inhibitingtumor cell proliferation, or reducing tumor growth.

The term “subject” as used herein includes all members of the animalkingdom including human. According to one embodiment, the subject is ahuman.

The expression “pharmaceutically acceptable” means compatible with thetreatment of subjects such as animals or humans.

The expression “pharmaceutically acceptable salt” means an acid additionsalt or basic addition salt which is suitable for or compatible with thetreatment of subjects such as animals or humans.

The expression “pharmaceutically acceptable acid addition salt” as usedherein means any non-toxic organic or inorganic salt of any compound ofthe present disclosure, or any of its intermediates. Illustrativeinorganic acids which form suitable salts include hydrochloric,hydrobromic, sulfuric and phosphoric acids, as well as metal salts suchas sodium monohydrogen orthophosphate and potassium hydrogen sulfate.Illustrative organic acids that form suitable salts include mono-, di-,and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic,succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonicacids such as p-toluene sulfonic and methanesulfonic acids. Either themono or di-acid salts can be formed, and such salts may exist in eithera hydrated, solvated or substantially anhydrous form. In general, theacid addition salts of the compounds of the present disclosure are moresoluble in water and various hydrophilic organic solvents, and generallydemonstrate higher melting points in comparison to their free baseforms. The selection of the appropriate salt will be known to oneskilled in the art. Other non-pharmaceutically acceptable salts, e.g.oxalates, may be used, for example, in the isolation of the compounds ofthe present disclosure, for laboratory use, or for subsequent conversionto a pharmaceutically acceptable acid addition salt. In embodiments ofthe present disclosure, the pharmaceutically acceptable acid additionsalt is the hydrochloride salt.

The term “pharmaceutically acceptable basic addition salt” as usedherein means any non-toxic organic or inorganic base addition salt ofany acid compound of the disclosure, or any of its intermediates. Acidiccompounds of the disclosure that may form a basic addition salt include,for example, where R is CO₂H. Illustrative inorganic bases which formsuitable salts include lithium, sodium, potassium, calcium, magnesium orbarium hydroxide. Illustrative organic bases which form suitable saltsinclude aliphatic, alicyclic or aromatic organic amines such asmethylamine, trimethylamine and picoline or ammonia. The selection ofthe appropriate salt will be known to a person skilled in the art. Othernon-pharmaceutically acceptable basic addition salts, may be used, forexample, in the isolation of the compounds of the disclosure, forlaboratory use, or for subsequent conversion to a pharmaceuticallyacceptable acid addition salt.

The formation of a desired compound salt is achieved using standardtechniques. For example, the neutral compound is treated with an acid orbase in a suitable solvent and the formed salt is isolated byfiltration, extraction or any other suitable method.

The expression “lipophilic active agent” as used herein refers to anactive agent which has an affinity for, or capability of dissolving in,lipids; i.e., non-water soluble oils, fats, sterols, triglycerides andthe like.

The term “lipid” as used herein refers to a synthetic ornaturally-occurring amphipathic compound which comprises a hydrophiliccomponent and a hydrophobic component. Lipids include, for example,fatty acids, neutral fats, phosphatides, glycolipids, aliphatic alcoholsand waxes, terpenes and steroids.

The expression “fatty acid(s)” as used herein refers to long chainaliphatic acids (alkanoic acids) of varying chain lengths, from aboutC12 to C22 (although both longer and shorter chain-length acids areknown). For example, the predominant chain lengths are about C16 toabout C22. The structure of a fatty acid is represented by a simplenotation system of “X:Y”, where X is the total number of carbon (C)atoms and Y is the number of double bonds.

Generally, fatty acids are classified as saturated or unsaturated. Theterm “saturated fatty acids” refers to those fatty acids that have no“double bonds” between their carbon backbone. In contrast, “unsaturatedfatty acids” are cis-isomers that have “double bonds” along their carbonbackbones. “Monounsaturated fatty acids” have only one “double bond”along the carbon backbone (e.g., usually between the 9th and 10th carbonatom as for palmitoleic acid (16:1) and oleic acid (18:1)), while“polyunsaturated fatty acids” (or “PUFAs”) have at least two doublebonds along the carbon backbone (e.g., between the 9th and 10th, and12th and 13th carbon atoms for linoleic acid (18:2); and between the 9thand 10th, 12th and 13th, and 15th and 16th for [alpha]-linolenic acid(18:3)).

“PUFAs” can be classified into two major families (depending on theposition (n) of the first double bond nearest the methyl end of thefatty acid carbon chain). Thus, the “[omega]-6 fatty acids” [omega]-6 orn-6) have the first unsaturated double bond six carbon atoms from theomega (methyl) end of the molecule and additionally have a total of twoor more double bonds, with each subsequent unsaturation occurring 3additional carbon atoms toward the carboxyl end of the molecule. Incontrast, the “[omega]-3 fatty acids” ([omega]-3 or n-3) have the firstunsaturated double bond three carbon atoms away from the omega end ofthe molecule and additionally have a total of three or more doublebonds, with each subsequent unsaturation occurring 3 additional carbonatoms toward the carboxyl end of the molecule.

Compounds of the present disclosure include radiolabeled forms, forexample, compounds labeled by incorporation within the structure ²H, ³H,¹⁴C, ¹⁵N, or a radioactive halogen such as ¹²⁵I. A radiolabeled compoundof the compounds of the present disclosure may be prepared usingstandard methods known in the art.

As used herein, and as well understood in the art, “treatment” or“treating” is an approach for obtaining beneficial or desired results,including clinical results. Beneficial or desired clinical results caninclude, but are not limited to, alleviation or amelioration of one ormore symptoms or conditions, diminishment of extent of disease,stabilized (i.e. not worsening) state of disease, preventing spread ofdisease, delay or slowing of disease progression, amelioration orpalliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” or “treating”can also mean prolonging survival as compared to expected survival ifnot receiving treatment.

In understanding the scope of the present disclosure, the term“comprising” and its derivatives, as used herein, are intended to beopen ended terms that specify the presence of the stated features,elements, components, groups, integers, and/or steps, but do not excludethe presence of other unstated features, elements, components, groups,integers and/or steps. The foregoing also applies to words havingsimilar meanings such as the terms, “including”, “having” and theirderivatives.

The sugar can be chosen from 5-carbon sugars and 6-carbon sugars.Non-limiting examples of 5-carbon sugar include ribose, arabinose,xylose, and lyxose. Non-limiting examples of 6-carbon sugar includeglucose, galactose, mannose, allose, gulose, idose, talose, and altrose.

The sugar phosphate can be chosen from monosaccharides (such asmannose-6-phosphate, glucose-6-phosphate, galactose-6-phosphate,mannose-l-phosphate, glucose-l-phosphate and galactose-l-phosphate),disaccharides (such as6-O-phosphoryl-a-D-mannopyranosyl-(1-2)-D-mannopyranose,6-O-phosphoryl-a-D-mannopyranosyl-(1-3)-mannopyranose,6-O-phosphoryl-a-D-mannopyranosyl-(1-6)-D-mannopyranose), trisaccharides(such as6-O-phosphoryl-a-D-mannopyranosyl-(1-2)-D-mannopyranosyl-(l-2)-D-mannopyranose),and higher linear or branched oligosaccharides (such aspentamannose-6-phosphate).

The amino acid can be chosen from alanine, arginine, asparagine,aspartic acid, cysteine, glutamine, glutamic acid, glycine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, and valine.

The peptide can be chosen from any possible combination of the aminoacids previously described.

For example, the compounds of the present disclosure can be of formulas:

Example 1 Preparation of Monoglyceride 1

Docosapentaenoic acid ethyl ester (compound 2) (10 g) and compound 3 (6g) were mixed together and heated at a temperature of 60° C. The enzyme(100 mg) was added and the reaction mixture was stirred at 60° C. undervacuum (18 mbar) or under nitrogen bubbling for 5 h. The reactionmixture was filtered and the enzyme was washed with ethanol 95% (20 ml).The acidic resin (500 mg) or organic acid was added to the ethanolsolution and heated to reflux for 18 h. The resin was removed byfiltration and the ethanol was evaporated in vacuo. The resulting crudeproduct was dissolved in a mixture of hexanes/ethyl acetate 90:10 (10ml) and silica gel (40 g) was added. The slurry was put on a frittedfunnel and eluted with hexanes/ethyl acetate 90:10 (150 ml) to removeunreacted starting material. A second elution with ethyl acetate (300ml) give, after evaporation in vacuo, the pure compound 1 (8.7 g) wastested in vitro on the cell viability assay and in an in vivo xenografttumor model.

Pure compounds 5 and 6 (see below) have also been successfully preparedby following the same procedure.

Example 2 Preparation of a Composition (Composition 1) ComprisingVarious Monoglycerides (Compounds 1, 5 and 6)

Composition 1 comprising compounds 1, 5 and 6 was prepared according tothe same procedure as previously described in Example 1. The startingmaterial was a mixture of compounds 2, 7, and 8 at respectively (10%,80%, and 10%). This starting material composition was sold by theCompany CRODA™ Chemical Europe Ltd. under the name INCROMEGA™ DHA 700 ESR. Thus, the obtained composition 1 contains 10% of compound 1, 80% ofcompound 5, and 10% of compound 6.

Example 3 Preparation of Monoglyceride 1

A fish oil (comprising pelagic fishes oil) (30 g) and compound 3 (6 g)were mixed together and heated at a temperature of 60° C. As illustratedin the above reaction scheme the fish oil can comprise a plurality oftriglycerides. The two R groups, which can be the same or different, canrepresent the chain of various fatty acids or other organic acidspresent in such an oil. In such triglycerides, at least one oxygen atomof the glycerol backbone forms an ester with an omega-3 fatty acids. Theenzyme (lipase) (100 mg) or KOH (1000 mg) was added and the reactionmixture was stirred at 60° C. for 3 h. The reaction mixture was filteredon a silica gel pad and the enzyme was washed with ethanol 95% (20 ml).The acidic resin (500 mg) or an acid was added to the ethanol solutionand heated to reflux for 18 h. The resin was removed by filtration andthe ethanol was evaporated in vacuo. The resulting crude product wasdistillated under reduced pressure to give the pure compound 1.

Various other oils rich in omega-3 and/or omega-6 fatty acids can beused. For example, vegetal oils (such as flaxseed oil, pumpkinseed oil,canola oil, soybean oil, walnut oil) and marine oils (such as algae oil,microalgae oil, phytoplankton oil, seal oil, krill oil, fish oil (forexample cod liver oil, salmon oil, tuna oil, shark oil, sardine oil,etc)) can be used.

Example 4

The cell viability assay is performed to measure the relative cellviability status of cancer cells upon exposure to test compounds incomparison to a positive control (etoposide) and a negative control(vehicule). Adherent cells growing in 96-well plates are exposed to testcompounds for 3 days (72 hours). Four cancer cell lines including lung,colon, prostate and breast types are used since these types of cancerpossess high incidence in human. Test compounds (composition 1comprising compounds 1, 5 and 6) as well as positive and negativecontrols were tested in parallel on the same culture plate. Allconditions are tested in triplicate. Apoptotic agents such as etoposideor epigallo-catechin-gallate are used as positive controls to kill cellswhereas the solvent (dimethylsulfoxide and water) is used as negativecontrols for basal determination. Inhibition of 50% of cell growthcompared to basal condition is the lower limit indicating a positivebiological response (considered as a hit). After the incubation time,total protein content is quantified following staining with the anionicdye sulforhodamine B (SRB). The detection of luminescence, emitted bySRB, is completed by a microplate reader. This method of detection isbased upon works published by Monks et al., in Journal of the NationalCancer Institute vol. 82 no. 13 (1991) p. 757, Skehan et al. in Journalof the National Cancer Institute vol. 82 no. 13 (1990) p. 1107 andRubinstein et al. in Journal of the National Cancer Institute vol. 82no. 13 (1990) p. 1113. The amount of luminescence is directlyproportional to the number of living cells in culture.

Cancer cells were grown in T-75 flask (Falcon) containing 20 ml ofappropriate culture medium, subcultured twice a week at 37° C., 5% CO₂,95% air and 100% relative humidity and maintained at low passage number(5 to 20), following manufacturer recommendations. The cell lines usedwere A-549 (human lung carcinoma), HCT-15 (human colon adenocarcinoma),BT-549 (human breast ductal carcinoma) and PC3 (human prostateadenocarcinoma). Cells were trypsinized using 0.25% trypsine (w/v)/0.53mM EDTA solution (Hyclone), counted and plated at densities between 1000and 3000 cells per well in flat bottom 96-well clear plates (BectonDickinson) in 100 μl of appropriate culture medium supplemented withfetal bovine serum (Hyclone). Culture plates were incubated at 37° C.,5% CO₂, 95% air and 100% relative humidity for 72 hours. At 20-30% ofcell confluence, 80 μl of appropriate culture medium was added to eachwell. 20 μl of either a solution of test compounds in 6 differentconcentration, drug for positive controls (at concentration of 29 mg/ml)or solvent (vehicle or water) for negative controls were added on top ofthe 180 μl of culture medium to obtain a final volume of 200 μl.Background plate containing the same volume of medium without cells wereincluded in each experiment. Microplates containing cells and testcompounds were incubated at 37° C., 5% CO₂, 95% air and 100% relativehumidity for 72 hours. One microplate for each cell line were fixed asdescribed below. These four microplates represented basal growth at timezero. After incubation time of 72 hours, cells were fixed with 50 μl ofcold (4° C.) 50% (w/v) trichloroacetic acid (TCA) added to the top of200 μl of culture medium. These microplates contained conditions ofgrowth control and test growth. Microplates were left 60 minutes at 4°C. and subsequently wash five times with 200 μl of deionized water.Microplates were left to dry at room temperature for at least 24 hours.All microplates were fixed with 100 μl of cold 0.4% (w/v) SRB dissolvedin 1% acetic acid solution in water added to each well containing cellsand left at room temperature for 10 minutes. Unbound SRB was removedwith successive washes (five times) with 200 μl of cold 1% acetic acidsolution in water. All microplates were left to dry at room temperaturefor at least 24 hours. Bound SRB to proteins was solubilised with theaddition of 100 μl of 10 mM cold unbuffered Tris-base solution (pH10.5). Microplates were left on a plate shaker for 5 minutes. Absorbancewas read at 515 nm using a 96-well plate Multiskan Spectrum luminescencereader (Thermo Electron Corporation). Data analysis was performed usingExcel 2003 and SigmaPlot 8.0 or GraphPadPrism 3.02 software. Percentgrowth inhibition was calculated using the absorbance measurements[Growth at time zero (T₀), growth control (C) plus the test growth atthe drug concentrations tested (T_(i)) as follows:(T_(i)−T₀)/(C−T₀)×100]. The results obtained are shown in FIGS. 1 to 4.

FIG. 1 represents the in vitro cell viability assay of six differentconcentrations of composition 1 on A-549 human lung cancer cell line.The positive control etoposide at 294 μg/ml shows 100% growthinhibition. The 50% growth inhibition is around 12.5 μg/ml of the testedcomposition.

FIG. 2 represents the in vitro cell viability assay of six differentconcentrations of composition 1 on PC-3 human prostate cancer cell line.The positive control etoposide at 294 μg/ml shows 100% growthinhibition. The 50% growth inhibition is around 6.25 μg/ml of the testedcomposition.

FIG. 3 represents the in vitro cell viability assay of six differentconcentrations of composition 1 on HCT-15 human colon cancer cell line.The positive control etoposide at 294 μg/ml shows 100% growthinhibition. The 50% growth inhibition is around 50 μg/ml of the testedcomposition.

FIG. 4 represents the in vitro cell viability assay of six differentconcentrations of composition 1 on BT-549 human breast cancer cell line.The positive control etoposide at 294 μg/ml shows 100% growthinhibition. The 50% growth inhibition is around 18.75 μg/ml of thetested composition.

The same tests have been carried out on the substantially purifiedcompound 1 and similar results were obtained.

Example 5

The in vivo xenograft tumor model protocol use eighteen (NU/NU-Fox1 nu)mice. After 3 days of acclimatization they were identified, weighed andselected into three cohorts randomly by weight. The animals received 3doses of treatment before inoculation of the MCF-7 cells. Dosingconsisted of 0.5 mL 3 days a week for a total of 7 weeks for eachcohort. The mice received a supplement of estrogen via an implant thatwas inserted subcutaneously in the subscapular region 48 hrs beforeMCF-7 cell inoculation. The animals were weighed once a week and tumorsmeasured 2 times per week. Blood samples (150 ml) were collected oncebefore treatment started, and subsequently every 2 weeks after cellinoculation and at termination. Plasma was collected as well as the RBCpellet, frozen and stored at −80° C. Animals were observed forappearance of tumor development. Once tumors were detected, tumorvolumes were assessed using the equation: V=L (mm)×W2 (mm)/2, where W iswidth and L is length of the tumor. At the end of the study survivinganimals were euthanized using isoflurane and cardiac puncture performedfor a terminal blood collection. Once tumors were detected, tumorvolumes were assessed using the equation: V=L (mm)×W2 (mm)/2, where W iswidth and L is length of the tumor. At the end of the study survivinganimals were euthanized using isoflurane and cardiac puncture performedfor a terminal blood collection. Once tumors were detected, tumorvolumes were assessed using the equation: V=L (mm)×W2 (mm)/2, where W iswidth and L is length of the tumor. At the end of the study survivinganimals were euthanized using isoflurane and cardiac puncture performedfor a terminal blood collection. Each animal was ear notched to identifytheir individual number and their tails marked for cage number. Animalsreceived food and water ad libitum during the study and 3 animals werehoused together per cage. The results obtained are shown in FIGS. 5 and6.

FIG. 5 represents a comparative in vivo efficacy study of composition 1,a fish oil (pelagic fishes) and a control (corn oil), carried out on(NU/NU-Fox1nu) mice xenograft model. In both positive control (fish oil)group and composition 1 group, an altered tumor kinetics was observed.In both cases, the tumor progression was reduced and this was observedto a considerably greater extent for the composition 1 group.

FIG. 6 represents the body weight of (NU/NU-Fox1nu) mice model in the invivo efficacy study of composition 1, a fish oil and a control (cornoil). The animal body weight was not affected by any of the treatments,suggesting that no apparent toxicity was observed at these doses.

Example 6

The relative human bioavailability of two different compositions(composition 2 and a fish oil) containing docosahexaenoic acid (DHA) andomega-3 docosapentaenoic acid (DPAω3) has been determined.

The fish oil comprises compounds 2 and 7 in about a 1:8 ratio (11% of 2and 89% of 7):

Composition 2 comprises compounds 1 and 5 and fish oil (comprisingcompounds 2 and 7 in a 1:2 ratio. In other words, composition 2comprises compounds 1 (3.6%), 2 (7.4%), 5 (29.4%), and 7 (59.6%):

Composition 2 was prepared according to the same procedure as previouslydescribed in Example 2.

The relative human bioavailability of these two different compositions(composition 2 and a fish oil) was determined by a pilot cross-overstudy on one healthy volunteer (male). The volunteer fasted for 12 hoursprior to the study. The participant consumed fish oil (capsules)equivalent to 3.0 g of DHA and 375 mg of DPAω3 as part of a breakfast.Controlled amount of boiled pasta was eaten after the 4 h time point. Aninitial blood sample (400 μl) was collected using a lancet at afingertip into heparin tubes followed by samples at 1, 2, 3, 4, 5, 6, 7and 8 hour after ingestion. Plasma was separated and immediatelyanalysed for fatty acid composition. Fourteen days later (washoutperiod), the procedure was repeated with composition 2 (capsules)equivalent to 3.0 g of DHA and 375 mg of DPAω3.

The results of this study are shown in FIGS. 7 and 8.

FIG. 7 shows the change in plasma docosahexaenoic acid (DHA)concentration of composition 2 compared to fish oil upon time over an 8hours study.

FIG. 8 shows the change in plasma omega-3 docosapentaenoic acid (DPAω3)concentration of composition 2 compared to fish oil upon time over an 8hours study.

In FIG. 7 the proportion of DHA in plasma (% DHA) increased slowly onlyafter 3 hours and reach a maximum of less than 2% after 8 hours whenfish oil was taken alone. With composition 2, the DHA increasedmoderately right after the ingestion and after 4 hours the DHA increasedrapidly to reach a plateau of more than 4.5% at 6 hours. After 8 hoursthe DHA variation is 4.5%.

In FIG. 8 the proportion of DPAω3 in plasma (% DPAω3) did not increaseafter 8 hours when fish oil was taken alone, this mean that DPAω3 wasnot absorbed in fish oil. With composition 2, the DPAω3 increasedmoderately right after the ingestion to reach a plateau of 0.5% at 3hours. After 8 hours the DPAω3 variation was more than 0.6%

The relative bioavailability of fatty acids from composition 2 comparedto fish oil is calculated with the formula:

${{relative}{\mspace{11mu}\;}{bioavailability}} = \frac{\lbrack{AUC}\rbrack_{A}*{dose}_{B}}{\lbrack{AUC}\rbrack_{B}*{dose}_{A}}$

The AUC (calculates area under the curve for concentration vs. timedata) is calculated using linear trapezoidal rule. The use of the lineartrapezoidal rule as a method for approximating the area under aconcentration-time curve is widely accepted. In this experiment, thedoses are the same. The calculated relative bioavailability ofdocosahexaenoic acid from composition 2 compared to fish oil from time 0to infinity is 3.72. Thus, when DHA is in the presence of compounds 1and/or 5, DHA is 3.72 times more bioavailable. For the relativebioavailability of DPAω3, no significant absorption was found with fishoil, compared to an increase of more than 0.6% after 8 hours withcomposition 2. The relative bioavailability of compound 1 and compound 5is calculated with the same formula:

${{relative}{\mspace{11mu}\;}{bioavailability}} = \frac{\lbrack{AUC}\rbrack_{A}*{dose}_{B}}{\lbrack{AUC}\rbrack_{B}*{dose}_{A}}$

The calculated relative bioavailability of compound 1 compared tocompound 5 from time 0 to infinity is 2.20. Thus, compound 1 is 2.2.times more bioavailable than compounds 5.

The compounds and compositions of the present disclosure can be used forenhancing bioavailability of at least one active agent. For example, theat elast one active agent can be a fatty acid or a derivative thereof(for example an C1-C6 ester (C1-C6 being the amount of carbon atoms inthe “alcohol” portion of the ester) of a fatty acid such as an ethylester) or a pharmaceutically acceptable salt thereof.

According to another aspect, there is provided a method for enhancingbioavailability of at least one active agent. The method comprisesmixing the at least one active agent with at least one compound of thepresent disclosure. For example, the at least one active agent can be alipophilic active agent such as a fatty acid or a derivative thereof(for example an C1-C6 ester (C1-C6 being the amount of carbon atoms inthe “alcohol” portion of the ester) of a fatty acid such as an ethylester) or a pharmaceutically acceptable salt thereof.

According to another aspect, there is provided a method for enhancingbioavailability of at least one active agent. The method comprisesadministering to a subject an effective amount of the at least oneactive agent and an effective amount of at least one compound of thepresent disclosure. For example, the at least one active agent can be alipophilic active agent such as a fatty acid or a derivative thereof(for example an C1-C6 ester (C1-C6 being the amount of carbon atoms inthe “alcohol” portion of the ester) of a fatty acid such as an ethylester) or a pharmaceutically acceptable salt thereof. For example, acomposition comprising an effective amount of the at least one activeagent and an effective amount of at least one compound of the presentdisclosure can be administered. Alternatively, the effective amount ofthe at least one active agent and the effective amount of the at leastone compound can be administered separately.

According to another aspect, there is provided a method for enhancingbioavailability of at least one active agent present in at least oneoil. The method comprises administering to a subject an effective amountof the at least one oil and an effective amount of at least one compoundof the present disclosure. For example, the at least one compoundpresent in the at least one oil can be a fatty acid or a derivativethereof (for example an C1-C6 ester (C1-C6 being the amount of carbonatoms in the “alcohol” portion of the ester) of a fatty acid such as anethyl ester) or a pharmaceutically acceptable salt thereof. For example,the oil can be a vegetable oil, fish oil, seal oil, microalgae oil,krill oil, crustacean oil (for example shrimps oil), mussels oil (forexample green lipped mussels oil), or mixtures thereof. For example, acomposition comprising an effective amount of the at least one oil andan effective amount of at least one compound of the present disclosurecan be administered. Alternatively, the effective amount of the at leastone oil and the effective amount of the at least one compound can beadministered separately.

For example, the compounds of the present disclosure can be used forenhancing bioavailability of at least one compound present in a fishoil. For example, the compounds of the present disclosure can be usedfor enhancing bioavailability of the ethyl ester of at least onecompound chosen from EPA, DPAω3, DPAω6, and DHA, and mixtures thereof.

Example 7

Composition 3 (comprising compounds 1 (11%) and 5 (89%)) at finalconcentration of 10 μg/ml, curcumin (5 μg/ml) and a 1:1 mixture ofcomposition 3 (10 μg/ml) and curcumin (5 μg/ml) in DMSO (1%) was usedfor the in vitro assay. Composition 3 prepared according to the sameprocedure as previously described in Example 2)

The in vitro assay allows evaluation of the potential anti-inflammatoryeffects of compounds on the induced-release of pro-inflammatory mediatorby monocyte cells. Typical human monocyte THP-1 cells, involved ininflammatory processes, are used in this assay. Measurement ofpro-inflammatory mediator TNF-α is performed by ELISA (manufactured byR&D Systems) with artificial induction of pro-inflammatory agents by LPS(E. Coli O55:B5) during 4 hours. Known anti-inflammatory agentdexametazone was used as positive control.

The results of this study are shown in FIG. 9.

In FIG. 9, no TNF-α was measured when no LPS is added to the monocyteTHP-1 cells incubated with compounds or vehicle. With 100 ng/ml of LPS,400 pg/ml of TNF-α was measured with the vehicle. With positive controldexametazone, only 125 pg/ml of TNF-α was measured, showing theanti-inflammatory effect of dexametazone. When composition 3 (10 μg/ml)was added, 275 pg/ml of TNF-α was measured and 100 pg/ml of TNF-α wasmeasured when curcumin (5 μg/ml) is added. When a mixture of composition3 and curcumin was added, less than 50 pg/ml of TNF-α was measured,showing a strong anti-inflammatory synergic effect.

According to another aspect, there is provided a method for treating aninflammatory disease comprising administering to a subject in needthereof an effective amount of at least one active agent and aneffective amount of at least one compound of the present disclosure. Forexample, a composition comprising an effective amount of the at leastone active agent and an effective amount of at least one compound of thepresent disclosure can be administered. Alternatively, the effectiveamount of the at least one active agent and the effective amount of theat least one compound can be administered separately.

While the disclosure has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the disclosure following, in general, theprinciples of the disclosure and including such departures from thepresent disclosure as come within known or customary practice within theart to which the disclosure pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

What is claimed is:
 1. A compound of formula (I), (II), (III), or (IV):

wherein in formula (I): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃ is O,NH, or S; R₁ and R₂ each independently represents —H, —C(O)NH₂,—S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl,—C1-C22 (amino)alkyl, —C3-C22 alkenyl, or —C3-C22 alkynyl, formula (II):X₁ is O, NH, or S; X₂ is O, NH, or S; X₃ is O, NH, or S; R₁ and R₂ eachindependently represents —H, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂, —C1-C22(oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl,—C3-C22 alkenyl, or —C3-C22 alkynyl, in formula (III): X₁ is O, NH, orS; X₂ is O, NH, or S; X₃ is O, NH, or S; R₁ is chosen from —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, and —C3-C22 alkynyl, and R₂ is chosen from —C(O)NH₂, —S(O)NH₂,—S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl,—C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22alkynyl, or R₁ is chosen from —C(O)NH₃, —S(O)NH₂, —S(O)₂NH₂, —C1-C22(oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl,—C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, and R₂ ischosen from —H, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl,—C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22(halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, in formula (IV): X₁is O, NH, or S; X₂ is O, NH, or S; X₃ is O, NH, or S; R₁ is chosen from—H, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl,—C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl,—C3-C22 alkenyl, and —C3-C22 alkynyl, and R₂ is chosen from —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, and —C3-C22 alkynyl, or R₁ is chosen from —C(O)NH₂, —S(O)NH₂,—S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl,—C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22alkynyl, and R₂ is chosen from —H, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂,—C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22(amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl,or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, wherein said compound is of formula (I) or (II).
 3. The compound ofclaim 2, wherein X₁ is O, X₂ is O, and X₃ is O.
 4. The compound of claim3, wherein R₁ and R₂ each independently represents —H, —C1-C22 alkyl,—C3-C22 alkenyl, or —C3-C22 alkynyl.
 5. The compound of claim 3, whereinR₁ is —H and R₂ is —H.
 6. The compound of claim 1, wherein said compoundis of formula (I) and wherein R₁ and R₂ each independently represents—H, —C1-C22 alkyl, —C3-C22 alkenyl, or —C3-C22 alkynyl.
 7. The compoundof claim 1, wherein said compound is of formula (II) and wherein R₁ andR₂ each independently represents —H, —C1-C22 alkyl, —C3-C22 alkenyl, or—C3-C22 alkynyl.
 8. The compound of claim 1, wherein said compound is offormula (I) wherein R₁ and R₂ are H.
 9. The compound of claim 1, whereinsaid compound is of formula (II) wherein R₁ and R₂ are H.
 10. Thecompound of claim 1, wherein said compound is:


11. The compound of claim 1, wherein said compound is:


12. The compound of claim 1, wherein said compound is chosen from:


13. A composition comprising at least two compounds as defined inclaim
 1. 14. A composition comprising the compound of claim 10 and:


15. A composition comprising the compound of claim 10 and at least onecompound chosen from:


16. A compound of formula (I) or (II):

wherein in formula (I): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃ is O,NH, or S; R₁ and R₂ each independently represents —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, five- to seven-membered aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein theamino acid is connected through its alpha carbon atom, —(CH₂)_(n)peptide wherein the peptide is connected through the alpha carbon atomof one of its amino acids, —CH₂OR₅, —C(O)OR₅, —C(O)NR₅, —S(O)₂NHR₅,—SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a sugar phosphate or R₁and R₂ are joined together so as to form a five- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine;R₅ is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl,—C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl,—C1-C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7) cycloalkylunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- toseven-membered non-aromatic heterocycle unsubstituted or substituted atleast one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, a three- to seven-membered aromatic heterocycleunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH₂)_(n) aminoacid wherein the amino acid is connected to the compound through itsalpha carbon atom, a —(CH₂)_(n) peptide wherein the peptide is connectedto the compound through the alpha carbon atom of one of its amino acids,a sugar or a sugar phosphate; and n is an integer having a value of 0,1, 2, 3, or 4, in formula (II): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃is O, NH, or S; R₁ and R₂ each independently represents —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, five- to seven-membered aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein theamino acid is connected through its alpha carbon atom, —(CH₂)_(n)peptide wherein the peptide is connected through the alpha carbon atomof one of its amino acids, —CH₂OR₅, —C(O)OR₅, —C(O)NR₅, —P(O)(OR₅)₂,—S(O)₂NHR₅, —SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a sugarphosphate or R₁ and R₂ are joined together so as to form a five- toseven-membered non-aromatic heterocycle unsubstituted or substitutedwith at least one substituent chosen from —C1-C22 alkyl, —C2-C22alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or athiocarbonyl imine; R₅ is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl,—C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl,—C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl,—C1-C22 (hydroxy)alkyl, —C1-C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7)cycloalkyl unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, athree- to seven-membered non-aromatic heterocycle unsubstituted orsubstituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22alkenyl, and —C2-C22 alkynyl, a three- to seven-membered aromaticheterocycle unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a—(CH₂)_(n) amino acid wherein the amino acid is connected to thecompound through its alpha carbon atom, a —(CH₂)_(n) peptide wherein thepeptide is connected to the compound through the alpha carbon atom ofone of its amino acids, a sugar or a sugar phosphate; and n is aninteger having a value of 0, 1, 2, 3, or 4, or a pharmaceuticallyacceptable salt thereof.
 17. The compound of claim 16, wherein saidcompound is a compound of formula:

or a pharmaceutically acceptable salt thereof.
 18. A compound of formula(I), (II), (III), or (IV):

wherein in formula (I): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃ is O,NH, or S; R₁ and R₂ each independently represents —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, five- to seven-membered aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from −C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein theamino acid is connected through its alpha carbon atom, —(CH₂)_(n)peptide wherein the peptide is connected through the alpha carbon atomof one of its amino acids, —CH₂OR₅, —C(O)OR₅, —C(O)NR₅, —S(O)₂NHR₅,—SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a sugar phosphate or R₁and R₂ are joined together so as to form a five- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine,R₅ is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl,—C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl,—C1-C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7) cycloalkylunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- toseven-membered non-aromatic heterocycle unsubstituted or substituted atleast one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, a three- to seven-membered aromatic heterocycleunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH₂)_(n) aminoacid wherein the amino acid is connected to the compound through itsalpha carbon atom, a —(CH₂)_(n) peptide wherein the peptide is connectedto the compound through the alpha carbon atom of one of its amino acids,a sugar or a sugar phosphate; and n is an integer having a value of 0,1, 2, 3, or 4, in formula (II): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃is O, NH, or S; R₁ and R₂ each independently represents —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, five- to seven-membered aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein theamino acid is connected through its alpha carbon atom, —(CH₂)_(n)peptide wherein the peptide is connected through the alpha carbon atomof one of its amino acids, —CH₂OR₅, —C(O)OR₅, —C(O)NR₅, —P(O)(OR₅)₂,—S(O)₂NHR₅, —SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a sugarphosphate or R₁ and R₂ are joined together so as to form a five- toseven-membered non-aromatic heterocycle unsubstituted or substitutedwith at least one substituent chosen from —C1-C22 alkyl, —C2-C22alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or athiocarbonyl imine; R₅ is —H, —C₁-C22 alkyl, —(C3-C7) cycloalkyl,—C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl,—C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl,—C1-C22 (hydroxy)alkyl, —C1-C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7)cycloalkyl unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, athree- to seven-membered non-aromatic heterocycle unsubstituted orsubstituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22alkenyl, and —C2-C22 alkynyl, a three- to seven-membered aromaticheterocycle unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a—(CH₂)_(n) amino acid wherein the amino acid is connected to thecompound through its alpha carbon atom, a —(CH₂)_(n) peptide wherein thepeptide is connected to the compound through the alpha carbon atom ofone of its amino acids, a sugar or a sugar phosphate; and n is aninteger having a value of 0, 1, 2, 3, or 4, in formula (III): X₁ is O,NH, or S; X₂ is O, NH, or S; X₃ is O, NH, or S; R₁ and R₂ eachindependently represents, —H, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂, —C1-C22(oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl,—C1-C22 (halo)alkyl, —C3-C22 alkenyl, C3-C22 alkynyl, —(C3-C7)cycloalkyl unsubstituted or substituted with at least one substituentchosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12aryl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl,three- to seven-membered non-aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromaticheterocycle unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,—(CH₂)_(n) amino acid wherein the amino acid is connected through itsalpha carbon atom, —(CH₂)_(n) peptide wherein the peptide is connectedthrough the alpha carbon atom of one of it amino acids, —CH₂OR₅,—C(O)OR₅, —C(O)NR₅, —S(O)₂NHR₅, —SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, asugar, or a sugar phosphate, wherein when R₁ is —H, R₂ is different than—H, and when R₂ is —H, R₁ is different than —H, or R₁ and R₂ are joinedtogether so as to form a five- to seven-membered non-aromaticheterocycle comprising at least one hetero atom chosen from nitrogen andsulfur, said heterocyle being unsubstituted or substituted with at leastone substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine;R₅ is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl,—C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl,—C1-C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7) cycloalkylunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- toseven-membered non-aromatic heterocycle unsubstituted or substituted atleast one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, a three- to seven-membered aromatic heterocycleunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH₂)_(n) aminoacid wherein the amino acid is connected to the compound through itsalpha carbon atom, a —(CH₂)_(n) peptide wherein the peptide is connectedto the compound through the alpha carbon atom of one of its amino acids,a sugar or a sugar phosphate; and n is an integer having a value of 0,1, 2, 3, or 4, in formula (IV): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃is O, NH, or S; R₁ and R₂ each independently represents, —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, five- to seven-membered aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein theamino acid is connected through its alpha carbon atom, —(CH₂)_(n)peptide wherein the peptide is connected through the alpha carbon atomof one of its amino acids, —CH₂OR₅, —C(O)OR₅, —C(O)OR₅, —S(O)₂NHR₅,—SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a sugar phosphate, whereinwhen R₁ is —H, R₂ is different than —H, and when R₂ is —H, R₁ isdifferent than —H, or R₁ and R₂ are joined together so as to form afive- to seven-membered non-aromatic heterocycle comprising at least onehetero atom chosen from nitrogen and sulfur, said heterocyle beingunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate,sulfate carbonyl group, or a thiocarbonyl imine; R₅ is —H, —C1-C22alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl,—C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, —C1-C22 alkoxy, —C1-C22(amino)alkyl, a —(C3-C7) cycloalkyl unsubstituted or substituted with atleast one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, a three- to seven-membered non-aromatic heterocycleunsubstituted or substituted at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyi, a three- toseven-membered aromatic heterocycle unsubstituted or substituted with atleast one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, a —(CH₂)_(n) amino acid wherein the amino acid isconnected to the compound through its alpha carbon atom, a —(CH₂)_(n)peptide wherein the peptide is connected to the compound through thealpha carbon atom of one of its amino acids, a sugar or a sugarphosphate; and n is an integer having a value of 0, 1, 2, 3, or 4, or apharmaceutically acceptable salt thereof.
 19. The compound of claim 18,wherein in formula (I): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃ is O,NH, or S; R₁ and R₂ each independently represents —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, five- to seven-membered aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein theamino acid is connected through its alpha carbon atom, —(CH₂)_(n)peptide wherein the peptide is connected through the alpha carbon atomof one of its amino acids, —CH₂OR₅, —C(O)OR₅, —C(O)NR₅, —S(O)₂NHR₅,—SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a sugar phosphate; R₅ is—H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12aryl, —C2-C22 alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, —C8-C22(aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, —C1-C22alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, a three- to seven-membered aromatic heterocycle unsubstitutedor substituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH₂)_(n) amino acid whereinthe amino acid is connected to the compound through its alpha carbonatom, a —(CH₂)_(n) peptide wherein the peptide is connected to thecompound through the alpha carbon atom of one of its amino acids, asugar or a sugar phosphate; and n is an integer having a value of 0, 1,2, 3, or 4, in formula (II): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃ isO, NH, or S; R₁ and R₂ each independently represents —H, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl,—C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted with at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, five- to seven-membered aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein theamino acid is connected through its alpha carbon atom, —(CH₂)_(n)peptide wherein the peptide is connected through the alpha carbon atomof one of its amino acids, —CH₂OR₅, —C(O)OR₅, —C(O)NR₅, —P(O)(OR₅)₂,—S(O)₂NHR₅, —SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, a sugar, or a sugarphosphate; R₅ is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22(halo)alkyl, —C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl, —C7-C22(aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22(hydroxy)alkyl, —C1-C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7)cycloalkyl unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, athree- to seven-membered non-aromatic heterocycle unsubstituted orsubstituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22alkenyl, and —C2-C22 alkynyl, a three- to seven-membered aromaticheterocycle unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a—(CH₂)_(n) amino acid wherein the amino acid is connected to thecompound through its alpha carbon atom, a —(CH₂)_(n) peptide wherein thepeptide is connected to the compound through the alpha carbon atom ofone of its amino acids, a sugar or a sugar phosphate; and n is aninteger having a value of 0, 1, 2, 3, or 4, in formula (III): X₁ is O,NH, or S; X₂ is O, NH, or S; X₃ is O, NH, or S; R₁ and R₂ eachindependently represents, —H, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂, —C1-C22(oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl,—C1-C22 (halo)alkyl, —C3-C22 alkenyl, C3-C22 alkynyl, —(C3-C7)cycloalkyl unsubstituted or substituted with at least one substituentchosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12aryl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl,three- to seven-membered non-aromatic heterocycle unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromaticheterocycle unsubstituted or substituted with at least one substituentchosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl,—(CH₂)_(n) amino acid wherein the amino acid is connected through itsalpha carbon atom, —(CH₂)_(n) peptide wherein the peptide is connectedthrough the alpha carbon atom of one of its amino acids, —CH₂OR₅,—C(O)OR₅, —C(O)NR₅, —S(O)₂NHR₅, —SOR₅, —S(O)₂R₅, -arylP(O)(OR₅)₂, asugar, or a sugar phosphate, wherein when R₁ is —H, R₂ is different than—H, and when R₂ is —H, R₁ is different than —H; R₅ is —H, —C1-C22 alkyl,—(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 alkenyl,—C2-C22 alkynyl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22(aryl)alkynyl, —C1-C22 (hydroxy)alkyl, —C1-C22 alkoxy, —C1-C22(amino)alkyl, a —(C3-C7) cycloalkyll unsubstituted or substituted withat least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, a three- to seven-membered non-aromatic heterocycleunsubstituted or substituted at least one substituent chosen from—C1-C22 alkyl; —C2-C22 alkenyl, and —C2-C22 alkynyl; a three- toseven-membered aromatic heterocycle unsubstituted or substituted with atleast one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, a —(CH₂)_(n) amino acid wherein the amino acid isconnected to the compound through its alpha carbon atom, a —(CH₂)_(n)peptide wherein the peptide is connected to the compound through thealpha carbon atom of one of its amino acids, a sugar or a sugarphosphate; and n is an integer having a value of 0, 1, 2, 3, or 4, informula (IV): X₁ is O, NH, or S; X₂ is O, NH, or S; X₃ is O, NH, or S;R₁ and R₂ each independently represents, —H, —C(O)NH₂, —S(O)NH₂,—S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl,—C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, C3-C22alkynyl, —(C3-C7) cycloalkyl unsubstituted or substituted with at leastone substituent chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl,—C8-C22 (aryl)alkynyl, three- to seven-membered non-aromatic heterocycleunsubstituted or substituted with at least one substituent chosen from—C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- toseven-membered aromatic heterocycle unsubstituted or substituted with atleast one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and—C2-C22 alkynyl, —(CH₂)_(n) amino acid wherein the amino acid isconnected through its alpha carbon atom, —(CH₂)_(n) peptide wherein thepeptide is connected through the alpha carbon atom of one of its aminoacids, —CH₂OR₅, —C(O)OR₅, —C(O)NR₅, —S(O)₂NHR₅, —SOR₅, —S(O)₂R₅,-arylP(O)(OR₅)₂, a sugar, or a sugar phosphate, wherein when R₁ is —H,R₂ is different than —H, and when R₂ is —H, R₁ is different than —H; R₅is —H, —C1-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12aryl, —C2-C22 alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, —C8-C22(aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, —C1-C22alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubstituted orsubstituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-memberednon-aromatic heterocycle unsubstituted or substituted at least onesubstituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22alkynyl, a three- to seven-membered aromatic heterocycle unsubstitutedor substituted with at least one substituent chosen from —C1-C22 alkyl,—C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH₂)_(n) amino acid whereinthe amino acid is connected to the compound through its alpha carbonatom, a —(CH₂)_(n) peptide wherein the peptide is connected to thecompound through the alpha carbon atom of one of its amino acids, asugar or a sugar phosphate; and n is an integer having a value of 0, 1,2, 3, or
 4. 20. The compound of claim 18, wherein in formula (I): X₁ isO, NH, or S; X₂ is O, NH, or S; X₃ is O, NH, or S; R₁ and R₂ eachindependently represents —H, —C(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl,—C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C3-C22alkenyl, or —C3-C22 alkynyl, in formula (II): X₁ is O, NH, or S; X₂ isO, NH, or S; X₃ is O, NH, or S; R₁ and R₂ each independently represents—H, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl,—C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C3-C22 alkenyl, or—C3-C22 alkynyl, in formula (III): X₁ is O, NH, or S, X₂ is O, NH, or S;X₃ is O, NH, or S; R₁ and R₂ each independently represents, —C(O)NH₂,—S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22(hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22alkenyl, or —C3-C22 alkynyl, in formula (IV): X₁ is O, NH, or S; X₂ isO, NH, or S; X₃ is O, NH, or S; and R₁ and R₂ each independentlyrepresents, —C(O)NH₂, —S(O)NH₂, —S(O)₂NH₂, —C1-C22 (oxy)alkyl, —C1-C22alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22(halo)alkyl, —C3-C22 alkenyl, or —C3-C22 alkynyl.
 21. The compound ofclaim 18, wherein said compound is: